Over 60% of American women now enter pregnancy either overweight or obese, which increases the risk for the infant to develop obesity, diabetes and cardiovascular disease in childhood and later in life. However, the mechanisms linking the in utero environment in maternal obesity to programming of the fetus for later disease remain poorly understood, which constitutes a major roadblock for the development of specific intervention strategies. Circulating levels of adiponectin are decreased in obese pregnant women and in our mouse model of maternal obesity. We have previously reported that adiponectin, in contrast to its well-known insulin- sensitizing effects in skeletal muscle and liver, inhibits placental insulin and mTOR signaling and amino acid transport. This effect is mediated by activation of trophoblast PPAR??signaling, which increases ceramide synthesis resulting in inhibition of IRS-1. Remarkably, in our novel model of maternal obesity, which shows extensive similarities with the human condition (elevated levels of maternal leptin, glucose intolerance, activation of placental insulin and mTOR signaling, increased placental nutrient transport and fetal overgrowth), restoration of normal circulating levels of adiponectin completely prevented placental dysfunction, fetal hyperglycemia and overgrowth. Our findings demonstrate that low circulating adiponectin in maternal obesity is mechanistically linked to increased placental nutrient transport and fetal growth. However, whether normalization of maternal adiponectin levels in pregnancy attenuates the long-term adverse metabolic and cardiovascular consequences of intrauterine exposure to maternal obesity in the offspring is unknown. Our central hypothesis is that adiponectin supplementation in late pregnancy prevents the development of metabolic and cardiovascular disease in the offspring in response to maternal obesity and that this effect is mediated by adiponectin receptor 2 (AdipoR2) in the placenta. This hypothesis is supported by compelling preliminary data including the demonstration that 3-month old male offspring of obese dams (1) develop obesity, glucose intolerance, hypertriglyceridemia and fatty liver; (2) have up-regulation of fetal cardiac genes, activation of cardiac insulin and mTOR signaling and left ventricular diastolic dysfunction and (3) these developmentally programmed changes are prevented by maternal adiponectin supplementation in pregnancy. Using mini-osmotic pumps, we will supplement adiponectin the last four days of pregnancy to lean and obese dams, with or without trophoblast-specific knock down of AdipoR2, and study male and female offspring at 3 and 6 months of age to address our hypothesis in three specific aims: Determine the effect of adiponectin supplementation in obese dams on offspring metabolism (Aim 1) and cardiovascular function (Aim 2) and to determine the mechanistic role of placental adiponectin receptors in fetal programming in maternal obesity (Aim 3). This work will have a significant and sustained impact on the field because it will lead to a better understanding of the mechanistic role of the placenta in mediating in utero programming and may lead to novel specific intervention strategies to alleviate the adverse effects of maternal obesity on the offspring.